Cocaine abuse and toxicities are serious threats to human health in the United States and the World. To date, there are no effective treatments for the abuse or toxicities associated with cocaine use. Agents targeting the sites of action of cocaine, such as the dopamine transporter, have met with limited success. Recently, it has been noted that sigma receptor antagonists can attenuate and block the toxic and the stimulant/rewarding effects of cocaine. Thus, the sigma receptor is a valid target for medication development for the treatment of cocaine toxicities and addiction. Sigma receptors exist as two distinct subtypes, sigma-1 and sigma-2. To date, only the sigma-1 receptor has been cloned. Sigma-1 receptors have been shown to be involved in the toxic and addictive effects of cocaine and are a logical target for the development of novel therapeutics. Although the involvement of sigma-2 receptors is not well-established, their involvement cannot be completely ruled out. This knowledge has been hampered by the availability of selective sigma-2 agents. However, existing data is highly suggestive of their involvement in the stimulant and toxic effects of cocaine. We therefore hypothesize that targeting sigma-1 and sigma-2 receptors, either in combination or through subtype-selective agents, can provide effective medications for treatment of cocaine toxicities and addiction. To date we have generated over thirty, structurally-related compounds based on a rational design (from known sigma antagonists) that have demonstrated high affinity for sigma-1 and sigma-2 receptors. In addition, some of these compounds have been evaluated in vivo and prevented cocaine-induced convulsions and locomotor activity. To test our hypothesis, the specific aims of the project are: 1) To develop, in a parallel synthesis fashion, novel sigma-1 and sigma-2 ligands with either selectivity for sigma-1, sigma-2, or a combination of affinities at each receptor. 2) To demonstrate these compounds like the preliminary examples have high affinity for sigma receptors and lack activity for other receptor types. 3) To develop three-dimensional pharmacophore models, based on our ligands that will help define the ligands selectivity profile and mode of binding at the receptor and promote father design of novel ligands. 4) To demonstrate the novel compounds attenuate cocaine-induced behaviors.